mTORC2 regulates renal tubule sodium uptake by promoting ENaC activity. Academic Article uri icon

Overview

abstract

  • The epithelial Na+ channel (ENaC) is essential for Na+ homeostasis, and dysregulation of this channel underlies many forms of hypertension. Recent studies suggest that mTOR regulates phosphorylation and activation of serum/glucocorticoid regulated kinase 1 (SGK1), which is known to inhibit ENaC internalization and degradation; however, it is not clear whether mTOR contributes to the regulation of renal tubule ion transport. Here, we evaluated the effect of selective mTOR inhibitors on kidney tubule Na+ and K+ transport in WT and Sgk1-/- mice, as well as in isolated collecting tubules. We found that 2 structurally distinct competitive inhibitors (PP242 and AZD8055), both of which prevent all mTOR-dependent phosphorylation, including that of SGK1, caused substantial natriuresis, but not kaliuresis, in WT mice, which indicates that mTOR preferentially influences ENaC function. PP242 also substantially inhibited Na+ currents in isolated perfused cortical collecting tubules. Accordingly, patch clamp studies on cortical tubule apical membranes revealed that mTOR inhibition markedly reduces ENaC activity, but does not alter activity of K+ inwardly rectifying channels (ROMK channels). Together, these results demonstrate that mTOR regulates kidney tubule ion handling and suggest that mTOR regulates Na+ homeostasis through SGK1-dependent modulation of ENaC activity.

publication date

  • November 21, 2014

Research

keywords

  • Epithelial Sodium Channels
  • Kidney Tubules, Distal
  • Multiprotein Complexes
  • Sodium
  • TOR Serine-Threonine Kinases

Identity

PubMed Central ID

  • PMC4382226

Scopus Document Identifier

  • 84920380185

Digital Object Identifier (DOI)

  • 10.1152/ajprenal.00381.2003

PubMed ID

  • 25415435

Additional Document Info

volume

  • 125

issue

  • 1